Novel quinazolinone derivatives 2-alkyl-3-(3&#39;-methylpyridine-2&#39;-yl)-5-chloro-4(3h)-quinazolinone

ABSTRACT

Novel quinazolinone derivatives, which exhibit central nervous system depressing activities such as tranquilizing, sedative, muscle-relaxing, spasmolytic and barbital potentiating activities with low toxicity, having the formula,   WHEREIN R is hydrogen, lower alkyl or halogenated lower alkyl, R1 is hydrogen, halogen, lower alkyl, halogenated lower alkyl, lower alkoxy or nitro, R2 is halogen, lower alkyl, halogenated lower alkyl, lower alkoxy or nitro, and X is chlorine or bromine are prepared by reacting an Nacylanthranilic acid derivative of the formula WHEREIN R and X have the same meanings as above and Z is hydroxyl, lower alkoxy, halogen or a group -OY where Y is an alkali metal, with an aminopyridine derivative of the formula WHEREIN R1 and R2 have the same meanings as defined above.

United States Patent 91 Yamamoto et al.

lnventors: Hisao Yamamoto; Shigeho Inaba, both of Nishinomiya; Seitetsu Arasaki; Isamu Maruyama, both of Minoo; Kei Takahashi, Takarazuka; Chiharu Saigo; Shigeru Sakai, both of Toyonaka, all of Japan [73] Assignee: Sumitomo Chemical Co., Ltd.,

Osaka, Japan [22] Filed: May 4, 1970 [21] Appl. No.:' 34,587

[30] Foreign Application Priority Data Jan. 23, 1967 Japan ..42/4725 Related US. Application Data [63] Continuation-impart of Ser. No. 683,813, Nov. 17,

1967, abandoned.

[52] US. Cl. ....260/256.4 Q, 260/296 R, 260/518 A, 424/251 [51] Int. Cl. ..C07d 51/48 [58] Field of Search ..260/256.4 Q

[56] References Cited UNITED STATES PATENTS 3,382,246 5/1968 Suter et a1. ..260/256.4 3,418,319 12/1968 Heusner et al. ..260/256.4

Primary Examiner-Alex Mazel Assistant Examiner-R. J. Gallagher Att0rneyWenderoth, Lind & Ponack [57] ABSTRACT Novel quinazolinone derivatives, which exhibit central E 1mtM0z nervous system depressing activities such astrinquilizing, sedative, muscle relaxing, spasmolytic and barbital potentiating activities with low toxicity, having the formula,

0-n ll: R1 X 5 NHCOR wherein R and X have the same meanings as above and Z is hydroxyl, lower alkoxy, halogen or a group where Y is an alkali metal, with an aminopyridine derivative of the formula wherein R and R have the same meanings as defined above.

3 Claims, No Drawings NOVEL QUINAZOLINONE DERIVATIVES 2- ALKYL-3-(3'-METHYLPYRlDINE-Z-YL)-5 CHLORO-4(3H)-QUINAZOLINONE This application is a continuation-in-part application of Ser. No. 683,813, filed Nov. 17, 1967, now abandoned.

The present invention relates to novel quinazolinone derivatives, and to pharmaceutical compositions containing such derivatives.

More particularly, the present invention pertains to novel quinazolinone derivatives, which are useful for medicines, ofthe formula,

wherein R and X have the same meanings as defined above, and

Z is hydroxyl, lower alkoxy, halogen or a group OY where Y is an alkali metal, with an aminopyridine derivative of the formula wherein R, and R have the same meanings as defined above.

The present quinazolinone derivatives 1 are novel and have not been reported in any literature. They exhibit central nervous system depressing activities such as tranquilizing, sedative, muscle relaxing, spasmolytic and barbital potentiating activities with low toxicity, even when orally administered. Thus, they are useful as medicaments.

The objective products may be produced advantageously by reacting an N-acylanthranilic acid derivative II with an aminopyridine derivative Ill in an inert solvent such as benzene, toluene, xylene, dioxane, nitrobenzene, pyridine or dimethylformamide, in the presence of phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, polyphosphoric acid or the like.

(III) LII v riers. For example, a l0-l00mg. dosage of 2-methyl-3 dimethyl-2-aminopyridine,

The N-acylanthranilic acid derivative 11 are exemplified by 2-formamido-6-chlorobenzoic acid, 2-formamido-6-bromobenzoic acid, 2-acetamido-6- chlorobenzoic acid, Z-acetamido-6-bromobenzoic acid, 2-propionamido-6-chlorobenzoic acid, 2- propionamido-6-bromobenzoic acid, Z-butyrylamido- 6-chlorobenzoic acid, Z-butyrylamido-tS-bromobenzoic acid, 2-isobutyrylamido-6-chlorobenzoic acid, 2-isobutyrylamido-6-bromobenzoic acid, 2-valerylamido-6- chlorobenzoic acid, 2-valerylamido-6-bromobenzoic acid, 2-isovalerylamido-6-chlorobenzoic acid, 2- isovalerylamido-6-bromobenzoic acid, 2- chloroacetamido-6-chlorobenzoic acid, 2- chloroacetamido-6-bromobenzoic acid, 2- chloropropionamido-o-chlorobenzoic acid, 2- chloropropionamido-6-bromobenzoic acid 2- chlorobutyryl-amido-6-chlorobenzoic acid, 2-

chlorobutyrylamido-6-bromobenzoic acid, and their alkali metal salts, their acid halides such as acid chlorides, their esters such as methyl esters, ethyl esters and t-butyl esters, etc.

Examples of the aminopyridine derivative ([11) are 3- 4-, 5- or 6-methyl-2-aminopyridine, 4-ethyl-2-aminopyridine, 2-, 4-, 5- or 6-methyl-3-aminopyridine, 2- or 3-methyl-4-aminopyridine, 5-chloro-2-aminopyridine, 5-bromo-2-aminopyridine, 5- or 6-chloro-3- aminopyridine, 3- or 5-nitro-2-aminopyridine, 3-nitro- 4-aminopyridine, 6-methoxy-3-aminopyridine, 4,6- 2,6-dimethyl-3- aminopyridine, 3-ethyl-6-methyl-Z-aminopyridine, 3,5- dichloro-2-aminopyridine, 3,5dibromo-2- aminopyridine, 3,5-dinitro-4-aminopyridine, 3-methyl- 5-nitro-2-aminopyridine, 4-methyl-5-nitro-2- aminopyridine, 3-methyl-5-nitro-2-aminopyridine, 5- nitro-3-bromo-2-aminopyridine, 3-trifluoromethyl-2- aminopyridine, etc.

Examples of the quinazolinone derivatives I of the:

2-methyl-3-(5 present invention include chloropyridine-2'-yl)-5-chloro-4( 3H )-quinazolinone, 2-methyl-3-(5-bromo-pyridine-2'-yl)-5-chloro-4(3H)- quinazolinone, 2-methyl-3-(6'-methylpyridine-2'-yl)- 5-chlor0-4(3H)-quinazolinone, 2-ethyl-3-(3-methylpyridine-2-yl)-5-chloro-4(3H)-quinazo1inone, 2-npropyl-3-( 3 -methylpyridine-2 -yl)-5-chloro-4 3H quinazolinone, 2-isopropyl-3-( 3 '-methylpyridine-2 yl )-5-chloro-4( 3H)-quinazolinone, 2-n-buty1-3-(3 methylpyridine-2-yl)-5-chloro-4(3H)-quinazolinone, 2-isobutyl-3-(3'-methylpyridine-2-yl)-5-chloro-4 (3H)-quinazo1inone, 2-methyl-3-(4',6-dimethylpyridine-2 '-yl )-5-chloro-4( 3 H )-quinazolinone, 2- chloromethyl-3-(3-methylpyridine-2'-yl)-5-chloro-4 (3H)-quinazolinone and their S-bromo isomers, etc. These quinazolinone derivatives are found to be much more potent than known quinazolinone derivatives and 2,2-di (carbamoyloxymethyl) pentane in tranquilizing activity.

The quinzaolinone derivatives of the present invention may be utilized in treating such mental disturbances as neurosis, insomnia, anxiety and the like. They can be administered parenterally or orally in therapeutic dosage forms with the specific dosage adjusted to individual needs, that is, in solid or liquid dosage forms such as tablets, dragees, capsules, suspensions, solutions, elixirs and the like with suitable carof the present invention are superior to known tranquilizing agents, the following experiments are presented.

I. EXPERIMENTAL A. Toxicity, Hypnotic Action and Sedative Action Each compound was administered to groups of l-20 mice, 18-22 g in body weight, at five dose levels or more, and LB HD and SD values were calculated as follows:

minimum of four dose levels according'to the method of Everett and Richards "6. M. Everett and R. K. Richards; J. Pharmacol. 81, 402 (I944). The animals were challenged with pentylenetetrazol, 110 mg/kg intraperitoneally, minutes after the oral administration of the test compound. The ED, was calculated by probit analysis, taking into account prevention of both convulsions and death.

II. RESULTS Results are summarized as shown in the following Tables.

Table l. Toxicity, Hypnotic Action and Sedative than one-half the rotating count in control (untreated) mice was used for calculation by the Litchfield-Wilcoxon method Litchfield and Wilcoxon; J. Phamacol. 96, 99 (1949).

B. Anti-convulsant effect of the test compounds.

I. Maximal electroshock seizures were induced by the technique of Swinyard et al. 'E. A. Swinyard, W.

. l5 v 1. LD,,. (50 percent lethal dose) The lethality was Action ofCompounds in Mice LDsn 11D) SD50 Compounds Route (mg/kg.) (mg./kg.) (mgr/kg.) Dso/SDso Quinazolinone derivatives of the present invention: 0 2 44 6 7 2-methyl-3-(3-methyl-pyridine-2-yl)-5-chloro-4(3H)quinazolin0ne 0&8 3352 2gE g 2ethyl'3- (3-methyl-pyridine-2-yl)-5-chloro-4 (3H) -quinaz0llnone l Z Known compounds:

2-ethyl3-(5-cl1Ior0-2-pyridyl)-4(3H)-quinazolin0nc P.o. 500 148 70 2. 1 2-methyl-3-(3-methyl-2-pyridyl)4(3H)-quinazolinone P.o. 500 143 82 1.5 Z-metllyl-3-(5-bromo-2'-pyridyl)-4(MD-quinazolinone P.o. 500 2158 2:338 2,2-di(carbamoyloxymethyl) pentanc 58 8? 350 2 N0TE.Syn1b0l indicates less than.

determined by the number of animals which died TABLE 2. ANTI-CONVULSANT ACTIVITY OF within 7 days following the administration of each com- COMPOUNDS IN MICE pound, and was calculated by a regression line based on Ann- Antldosage and lethality according to the Litchfield-Wllelectroshock pentylenecoxon method Litchfield and Wilcoxon; J. Compounds seizlhr e) (tetrjikzog Phamacol. 96,99 1949 $5 "5 I 2'. HD (50 percent hypnotic dose) The hypnotic activity was determined based on the number of Quinazolinone derivatives of the present invention: animals exhibiting loss of righting reflex for over 20 seconds, and calculated by the Litchfield-Wllcoxon pyridine-2'-yl)-5- 38 l5 method Litchfield and Wilcoxon; J. Phamacol. 96, (25-68) (lo-l7) 99 1949 2-ethyl-3-(3'methyl- 'd -2'- l -5- 46 25 3. SD (50% sedative dose) The motor activity of L, ,,',',,1,"j ,l, mlce was determined based on the number of rotations none C d in a rotatingcage for 15 minutes afterladministering the compounds, and the number of animals which was less 2'- ridyl)-4( 3 3 quinazolinone exhibit greater anti-convulsant activity than the known quinazolinone derivatives.

Further, 2-methyl-3-(3-methylpyridine-2-yl) -5- chloro-4(3H)-quinazolinone of the present invention had hexobarbital potentiation activity equal to that of 2,2-di(carbamoyloxymethyl)pentane.

Practical embodiments of this invention are presented in the following examples, which are intended only for illustration and not as limiting the scope of the invention.

EXAMPLE 1 To a mixture of 5 g. of 2-acetamido-6-chlorobenzoic acid and 5.3 g. of 2amino-5-ch1oropyridine in 80 ml. of xylene was added dropwise a solution of 1.5 g. of phosphorus trichloride in 20 ml. of xylene under cooling. The resultant mixture was heated under reflux for 25 hours. After cooling, .65 ml. of percent aqueous solution of sodium carbonate was added to the reaction mixture, and the mixture was stirred. The insoluble material was collected by filtration, washed with water and xylene in order and dried to give 3.5 g. of 2-methyl- 3 5 '-chloropyridine-2 '-yl )-5-chloro-4( 3H )-quinazolinone melting at 191 to 192C. Recrystallization from ethanol gave white crystals melting at 193C.

Anal. Calcd. for C ll Cl N Oz C, 54.90%; N, 13.73%; C1, 23.20%. Found: C, 55.07%; N, 13.57%; Cl 23.04%.

UV: x5535 232,271, 279sh, 305sh, 317, 329mg.

EXAMPLE 2 To a mixture of 10.7 g. of 2-acetamido-6- chlorobenzoic acid and 9.5 g. of 2-amino-5- bromopyridine in 125 ml. of xylene was added dropwise a solution of 2.9 g. of phosphorus trichloride in 10 ml. of xylene under cooling, and the resultant mixture was heated under reflux for 17.5 hours. After cooling, 50 ml. of 10 percent aqueous solution of potassium carbonate was added to the reaction mixture, and then the mixture was stirred. The insoluble material was collected by filtration, washed with water and xylene in order and dried to give 13.3 g. of 2-methyl-3-(5'- bromopyridine-2-yl)-5-chloro-4(3H)-quinazolinone, which was recrystallized from benzene to give pale green prisms melting at 219 to 219.5C.

Anal. Calcd. for C H ClBrN,O: C, 47.96%; N, 12.14%; halogen, 20.22%. Found: C, 47.90%; N, 11.99%; halogen, 20.09%.

UV: Afiffif 234, 271, 279, 317, 327 mu.

EXAMPLE 3 To a mixture of 5 g. of 2-acetamido-6-ch1orobenzoic acid and 2.8 g. of 2-amino-6-methylpyridine in 80 ml. of xylene was added dropwise a solution of 1.5 g. of phosphorus trichloride in 15 ml. of xylene under cooling with ice, and the resultant mixture was heated under reflux for 25 hours. After cooling, 10 percent aqueous solution of sodium carbonate was added to the reaction mixture, and the mixture was stirred. The insoluble material was collected by filtration, washed with water and xylene in order and dried to give 3.9 g. of 2-methyl-3-(6'-methylpyridine-2'-yl)-5-chloro-4(3 H )-quinazolin'one melting at 193 to 194C. Recrystallization from ethanol gave crystals melting at 194 to 195C. From the mother liquor, an additional 1.1 g. of product was obtained.

Anal. Calcd. for C, -,H,,ClN O: C, 63.05%; N, 14.79%; Cl, 12.43%. Found: C, 62.79%; N, 14.79%, Cl, 12.43%. Found: C, 62.79%; N, 14.65%; Cl, 25.45%.

1R: u 1698, 1622, 1604 cm.

uv. $1 232, 271,279511, 305sh, 317,329 mp.

max

EXAMPLE 4 To a mixture of 5 g. of 2-acetamido-6-ehlorobenzoic acid and 2.8 g. of 2-amino-3-methylpyridine in ml. of xylene was added dropwise a solution of 1.5 g. of phosphorus trichloride in 15 ml. of xylene under cooling with ice, and the resultant mixture was heated under reflux for 25 hours. After cooling, 10 percent aqueous solution of sodium carbonate was added to the reaction mixture, and the mixture was stirred. The xylene layer was separated, dried over anhydrous potassium carbonate and concentrated under reduced pressure. The oily residue was solidified on trituration with water to give a solid. The solid was collected by filtration, washed with water and driedto give 4.4 g. of crude 2-methyl-3-(3-methylpyridine-2-yl)-5-chloro- 4(3l-l)-quinazolinone. Recrystallization from ethanol give pale yellow prisms melting at 159 to 160C.

Anal. Calcd. for C l-l ClN Oz C, 63.05%; N, 14.71%; C1, 12.43%. Found: C, 62.85%; N, 14.78%; Cl, 12.29%.

IR: v"-"" 1675, 1615, 1600 cm.

max

UV: Afifgfl' 232, 270, 280,317, 330 mu.

EXAMPLE 5 'To a mixture of 5 g. of 2-acetamido-6-chlorobenzoic acid and 2.8 g. of 2-amino-3-methylpyridine in 80 ml. of xylene was added dropwise a solution of 1.5 g. of phosphorus trichloride in 15 ml. of xylene under cooling, and the resultant mixture was heated under reflux for 15 hours. After cooling, 10 g aqueous solution of sodium carbonate was added to the reaction mixture, and the mixture was stirred. The insoluble material is collected by filtration, washed with water and xylene in order and dried to give 2.9 g. of 2-methyl-3-(5 '-methylpyridine-2'-yl)--5-chloro-4(3H)-quinazolinone melting at 181 to 182C. Recrystallization from ethanol gave crystals melting at 184to 185C. From the mother liquor, an additional 1.7 g. of product was obtained.

' Anal. Calcd. for c n cm o. C, 63.05%; N, 14.71%;Cl, 12.43%. Found: C, 63.34%; N, 14.84%; C1, 12.64%.

1R: vilil'l 1685, 1613, 1590 cm.

UV: M1121 233, 271, 280, 305sh, 317, 328 mu.

EXAMPLE 6 To a mixture of 5 g. of 2racetamido-6-chlorobenzoic acid and 3.2 g. of 2-amino-4,6-dimethylpyridine in 80 ml. of xylene was added dropwise a solution of 1.5 g. of phosphorus trichloride in 15 ml. of xylene under cooling, and the resultant mixture was heated under reflux for 15 hours. After cooling, 10 percent aqueous solution of sodium carbonate was added to the reaction ninx EXAMPLE 7 According to the similar procedure of Example 6, there was obtained 2-methyl-3-(6'-methoxypyridine-3 -yl)--chloro-4(3l-l)-quinazolinone melting at 122 to 124C. from 5.3 g. of 2-acetamido-6-chlorobenzoic acid and 3.5 g. of 3-amino-6-methoxypyridine.

Anal. Calcd. for CH zClN3O2l C, 59.71%; N, 13.93%; Cl, 11.75%. Found: C, 59.70%; N, 13.51%; Cl, 1 1.31%.

UV: Ail'l'i 232, 272, 280, 305, 317, 329 mp.

EXAMPLE 8 To a mixture of 2-acetamido-6-chlorobenzoic acid (5.3 g.) and 3.6 g. of 3-amino-2-chloropyridine in 100 ml. ofxylene was added dropwise a solution of 1.5 g. of phosphorus trichloride in 10 ml. of xylene under cooling with ice, and the resultant mixture was heated under reflux for 7 hours.After cooling, 10 percent aqueous solution of sodium carbonate was added to the reaction mixture, and the mixture was stirred. The insoluble material was collected by filtration, washed with water and xylene in orderand dried to give 4.6 g. of crude 2-methyl-3-(2'-chloropyridine-3'-yl)-5- chloro-4 (3H)-quinazo1inone melting at 150 to 151.5C. Recrystallization from ethanol gave crystals melting at l56.0 to 156.5C. From the mother liquor an additional 1.8 g. of product was obtained. The melting point was 156.0 to 156.5C.

Anal. Calcd. for C H Cl,N O: C, 54.92%; N, 13.73%; Cl, 23.16%. Found: C, 54.82%; N, 13.54%; C1, 23.13%.

1R: 1 1339, 1685, 1619, 1599 cm".

EXAMPLE 9 To a mixture of 6.8 g. of 2-propionamido-6-chlorobenzoic acid and 3.6 g. of 2-amino-3-methylpyridine in 1 10 ml. of xylenewas added dropwise a solution of 1.9 g. of phosphorus trichloride in 10 ml. of xylene under cooling with ice, and the mixture was heated under reflux for 13 hours. After cooling, 10 percent aqueous lized on adding ethanol and cooling to give 2-ethyl-3-(F; '-methylpyridine-2'-yl )-5-chloro-4( 3 H )-quinazolinone?, which was recrystallized from ether-hexane, m.p. 139- 140C.

Anal. Calculated for C H CIN O: C, 64.16%; H, 4.71%; N, 14.03%; Cl, 11.84%. Found: C, 64.25%; H, 4.62%; N, 14.15%; Cl, 12.04%

EXAMPLE 10 To a mixture of 5 g. of 2-acetamido-6-chlorobenzoic acid and 2.8 g. of 2-amino-4-methylpyridine in ml. of xylene was added dropwise a solution of 1.5 g. of phosphorus trichloride in 10 m1. of xylene under cool ing with ice, and the mixture was heated under reflux for 15 hours. After cooling, 10 percent aqueous sodium carbonate solution was added to the reaction mixture ll 01 O wherein R is methyl or ethyl. 2. A compound according to claim 1, namely2- methyl-3-( 3 '-methylpyridine-2 '-yl)-5-chloro-4( 3H quinazolinone. I

3. A compound according to claim 1, namely 2 ethyl-3-(3-methylpyridine-2'-yl)-5-chloro-4(3H)- quinazolinone.

to give 2-methyl-3-(4-methyl- 

2. A compound according to claim 1, namely 2-methyl-3-(3''-methylpyridine-2''-yl)-5-chloro-4(3H)-quinazolinone.
 3. A compound according to claim 1, namely 2-ethyl-3-(3''-methylpyridine-2''-yl)-5-chloro-4(3H)-quinazolinone. 